Synthesis of 10-isogonenes and derivatives thereof



United States Patent O 3,470,215 SYNTHESIS OF 10-ISOGONENES ANDDERIVATIVES THEREOF George C. Buzby, Jr., Philadelphia, and HerchelSmith, Wayne, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware N Drawing. Filed Apr. 4, 1967,Ser. No. 628,274 Int. Cl. C07c 169/66, 169/22; A61k 27/00 US. Cl.260-3973 10 Claims ABSCT OF THE DISCLOSURE The compounds of the class of,13-dialkyl--isogonan- 3-one compounds useful as anti-androgenic agents.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION More particularly,this invention is directed to a compound of the formula:

wherein (5) represents the alpha or beta positions; R and R are eachalkyl groups of less than 5 carbon atoms; R is selected from the groupconsisting of hydroxy and acyloxy; R is selected from the groupconsisting of hydro gen, and alkyl of less than 5 carbon atoms, andtogether R and R is 0x0 0).

The final products of this invention are physiologically activesubstances which are useful as anti-androgenic agents. Hence, they maybe administered in lieu of known anti-androgenic agents, such asA-norprogesterone.

The compounds may be formulated for such administration based on theactivity of the particular compound and the requirements of the patient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Patented Sept. 30, 1969 "iceAccording to one feature of this invention, 13-alkylgona-4,9-diene-3-onecompounds of Formula II are reduced with hydrogen in the presence of anoble metal catalyst, such as palladium oxide on strontium carbonate, inan inert organic solvent to yield the novel intermediates13-alkyl-10u-gon-4-en-3-one compounds of Formula HI.

The initial 13-alkylgona-4,9-dien-3-one compounds (II) may be preparedin accordance with any prior art processes such as described in saidBelgian Patent No. 638,080.

The l3-alkyl-10a-gon-4-en-3-ones (III) are treated with an organo-metalcompound, such as a Grignard compound, to yield the5,l3-dialkyl-10-isogonan-3-one compounds of Formula IV, which are thepharmacologically active products of this invention.

To prepare the 3,17-dione compounds of this invention, the corresponding5,13-dialkyl-17-hydroxy-10-isogonan-3- one compounds are oxidized by anyconventional method, such as treatment with Jones reagent.

The following examples illustrate the invention (all temperatures beingin centig-rade):

EXAMPLE 1 13,17-diethyl-17/i-hydroxy-10a-gon-4-en-3-one 1.0 gm. of13,17-diethyl-17fl-hydroxygona-4,9-dien-3- one in 30 ml. of benzene isadded to 300 mg. of 2% PdO/SrCO previously reduced. Uptake of one moleof hydrogen requires one half hour. The catalyst is filtered, thefiltrate concentrated to dryness and the solid residue is trituratedwith ether to yield 0.275 gm. of 13,17-diethyl-17fi-hydroxy-10a-gon-4-en-3-one, M.P. -187 Recrystallization from ethylacetate gave 0.220 gm. of pure product, M.P. 189-191";

A51 2.9, 6.05m K51112 1 1 (615,825).

Analysis.Calcd. for C H O requires: C, 79.70; H, 10.19. Found: C, 79.48;H, 10.11.

EXAMPLE 2 13,17-diethy1-17/i-hydroxy-10u-gon-4-en-3-one,

17-acetate Following the procedure of Example 1, but substitutingl3,17-diethyl-17 3-hydroxygona-4,9-dien-3-one, 17-acetate for13,17-diethyl-17,9-hydroxygona-4,9-dien-3-one there is obtained 13,17diethyl-17,8-hydroxy-10a-gon-4-en-3-one, 17-acetate.

EXAMPLE 3 13-ethyl-17-methyl-17,8-hydroxy-10a-gon-4-en-3-one Followingthe procedure of Example 1, but substituting 13ethyl-17-methyl-l7fi-hydroxygona-4,9-dien-3-one for13,17-diethyl-17I3-hydroxygona-4,9-dien-3-one there is obtained 13ethyl-17-methyl-17 3-hydroxy-10a-gon-4-en-3- one.

EXAMPLE 4 13-ethyl-17-propyl-17fi-hydroxy-10a-gon-4-en-3-one Followingthe procedure of Example 1, but substituting 13ethyl-17-propyl-17fl-hydroxygona-4,9-dien-3-one for13,17-diethyl-17fl-hydroxygona-4,9-dien-3-one there is ob- 3 tained 13ethyl-17-propyl-17p-hydroxy-10a-gon-4-en-3- one.

EXAMPLE 5 13-ethyl-17-butyl-17fl-hydroxy-10a-gon-4-en-3-one Followingthe procedure of Example 1, but substituting 13ethyl-17-butyl-175-hydroxygona-4,9-dien-3-0ne for13,17-diethyl-17B-hydroxygona-4,9-dien-3-one, there is obtained 13ethyl-17-butyl-17/3-hydroxy-10a-gon-4-en-3- one.

EXAMPLE 6 13-propyl-l7-methyl-17/S-hydroxy-10a-gon-4-en-3-one Followingthe procedure of Example 1, but substituting 13 propyl 17methyl-17fi-hydroxygona-4,9-dien-3- one for 13,17 diethyl17fi-hydroxygona-4,9-dien-3-one, there is obtained13-propyl-17-methyl-l7fi-hydroxy-l0agon-4-en-3-one.

EXAMPLE 7 13-butyl-17-methyl-17 fi-hydroxy-u-gon-4-en-3-one Followingthe procedure of Example 1, but substituting 13 butyl 17 methyl17;8-hydroxygona-4,94lien-3-one for 13,17 diethyl1713-hydr0xygona-4,9-dien-3-one there is obtained 13 butyl 17methyl-17p-hydroxy-10a-gon- 4-en-3-one.

EXAMPLE 8 13,l7-diethyl-l7p-hydroxy-5-methyl-10a-gonan-3-one 0.390 gm.of l3,l7-diethyl-17fl-hydroxy-10a-gon-4-en- 3-one in 10 ml. of drytetrahydrofuran is added to ml. of dry tetrahydrofuran containing 10 ml.of 3 M methyl magnesium bromide and CuCl (.40 g.) at 18. The reaction,under N is allowed to reach room temperature, stirred for A hour andpoured into brine saturated with hydrogen chloride. Ether extraction,washing of the ether layer, drying and removal of solvent yields a solidwhich is chromatographed on 26 gm. of fullers earth. Elution with 3%ether-benzene followed by recrystallization from ether-hexane then againfrom ether gave 0.09 g. of 13,17- diethyl 17fthydroxy-S-methyl-l0a-gonan-3-one, M.P. 186-187 0.,

Analysis.--Calcd. for C H O requires: C, 79.46; H, 10.92. Found: C,79.73; H, 10.68.

Similarly, by following the procedure of Example 8, but substitutinganother Grignard reagent for the methyl magnesium bromide, such as ethylmagnesium bromide, propyl magnesium bromide, butyl magnesium bromide,and the like, the corresponding S-alkyl derivative is obtained.

EXAMPLE 9 13,17-diethyl-17B-hydroxy-5-methyl-10a-gonan-3-one, 17-acetateFollowing the procedure of Example 8, but substituting 13,17 diethyl 17Bhydroxy 10a-gon-4-en-3-one, 17- acetate for 13,17 diethyl17fl-hydroxy-10a-gon-4-en-3- one there is obtained13,17-diethyl-17fi-hydroxy-5-methyl- 10a-gonan-3-one, 17-acetate.

EXAMPLE 10 13-ethyl-17-methyl-17fl-hydroxy-S-methyhlOa-gonan- 3-oneFollowing the procedure of Example 8, but substituting 13 ethyl l7methyl 17fl-hydroxy-l0a-gon-4-en-3-one for 13,17 diethyl 17Bhydroxy-10a-gon-4-en-3-one there is obtained 13 ethyl17-methyl-17p-hydroxy-5- methyl-l0u-gonan-3-one.

H 4 EXAMPLE 11 13-ethyl-17-propyl-17fi-hydroxy-5-methyl-10a-g0nan 3-oneFollowing the procedure of Example 8, but substituting 13 ethyl 17propyl 17fi-hydroxy-l0a-gon-4-en-3-one for 13,17 diethyl 17/3hydroxy-10a-gon-4-en-3-one, there is obtained 13 ethyl 17propyl-17fl-hydroxy-5- methyl-10a-gonan-3-one.

EXAMPLE l2 13-ethyl-l7 butyl-17p-hydroxy-5-metl1yl-10a-gonan- 3-0neFollowing the procedure of Example 8, but substituting l3 ethyl 17 butyl17/8-hydroxy-10a-gon-4-en-3-one for 13,17 diethyl 17,6hydroxy-10u-gon-4-en-3-one, there is obtained13-ethyl-17-butyl-17fl-hydroxy-5-methyl- 10a-gonan-3-one.

EXAMPLE 13 13-propyl-17-methyl-17,6-hydroxy-5-methyl-10a-gonan- 3-oneFollowing the procedure of Example 8, but substituting 13 propyl 17methyl l7B-hydroxy-lOwgon-4-en-3- one for 13,17 diethyl 173-hydroxy-10a-gon-4-en-3-one there is obtained 13 propyl 17methyl-17fl-hydroxy-5- methyl-10a-gonan-3-one.

EXAMPLE l4 Following the procedure of Example 8, but substituting 13butyl 17 methyl 17fi-hydroxy-10a-gon-4-en-3- one for 13,17 diethyl17,3-hydroxy-l0u-gon-4-en-3-one, there is obtained 13 butyl 17methyl-17,8-hydroxy-5- mGthYI-IOa-g0118I1-3-OH6.

EXAMPLE 15 13-ethyl-5-methyl-10agonane-3,17-dione (A) Following theprocedure of Example 8, but substituting l3 ethylhydroxy-10a-gon-4-en-3-one for 13,17 diethyl 17/3hydroxy-10a-gon-4-en-3-one there is obtained 13 ethyl17,8-hydroxy-5-methyl-10ugonan-3-one.

(B) Treatment of the resulting 13-ethy1-17fl-hydroxy-5-methyl-10a-gonan-3-one with a Jones reagent yields 13-ethyl5-methyl-10a-gonane-3,l7-dione.

It is understood that either the dl-steroids or the specific dorl-isomers may be employed as starting materials with like results.

It is further understood that both 5aand SB-steroids are included withinthe scope of the invention.

What is claimed is:

1. A compound of the formula where R is an alkyl of 2 to 4 carbon atoms;R is an alkyl of less than 5 carbon atoms; R is selected from the groupconsisting of hydroxy and lower acyloxy; R is selected from the groupconsisting of hydrogen and alkyl of less than 5 carbon atoms; andtogether R and R is oxo(=0).

2. A compound according to claim 1 having the structural formula OH [mmH I Q l a 0....

wherein R is an alkyl group of 2 to 4 carbon atoms; R is selected fromthe group consisting of hydroxy and lower acyloxy; while R is selectedfrom the group consisting of hydrogen, alkyl of less than 5 carbonatoms.

9. A compound according to claim 8 that is13,17-diethyl-17B-hydroxy-10u-gon-4-en-3-one.

10. A process for preparing the compounds of claim 1 which comprises thesteps of:

(A) Catalytically reducing a compound of the formula wherein R, R and Rare as hereinbefore defined in claim 8, so as to form the compound ofclaim 8, and then,

(B) treating the compound formed with a lower alkyl magnesium halide.

References Cited UNITED STATES PATENTS 9/1967 Farkas 260397.3

OTHER REFERENCES Mori, Chem. and Pharm. Bull. 10, May 1962, pp. 382- 86.

ELBERT ROBERTS, Primary Examiner US. Cl. X.R.

